Our primary aim is the development of a coordinated set of new reagents for peptide synthesis, comprising new amide forming reagents, protective groups which can be removed under exceedingly mild conditions, and protective groups which can be used to achieve affinity isolation and solubilization. Primary approaches to amide formation include safety-catch activation and prior amine capture. Independently usable affinity isolation procedures or "handles" are to be used to achieve isolation and purification of products from coupling reactions without recourse to chromatography or crystallization. Protective groups are sought which can be removed with special reagents under conditions close to physiological, minimizing damage to peptide products. A key strategy for amide formation between large peptide fragments involves prior thiol capture, which forms amide bonds to peptides bearing N-terminal cysteine residues.